This application presents a proposal to extend for a third five-year funding period a Program Project Grant that has supported a network of interacting research groups in the Boston-Cambridge area whose research is focused on the genetic, molecular, and cellular mechanisms leading to the formation of human breast cancers. The findings of this research are increasingly being applied and related to the problems of clinical breast cancer development, diagnosis, and treatment. As described below in this proposal, this Program has fostered fruitful interactions between the participating research groups in the past and promises to do so in the future. Much of the synergy that has arisen in the past among these groups and is proposed for the future funding period has derived from the fact that the participating groups have complementary interests, thereby attacking the breast cancer problem using a number of distinct experimental approaches. Included among these complementary strategies are studies of (I) how defects in the BRCA1&2 proteins lead to compromised DNA repair and resulting basaloid carcinomas of the breast; (ii) how D-type cyclins drive the proliferation of mammary epithelial cells in as many as half of human breast cancers; (iii) how various regulators of mammary epithelial cell biology affect the apoptosis of these cells and their behavior early in breast cancer development; (iv) how estrogen and progesterone receptors affect the biology of mammary epithelial cells; (v) how breast cancer cells acquire the ability to metastasize and succeed in founding macroscopic metastases at distant tissue sites; (vi) how changes of gene expression patterns provide indications of the nature of the initial steps of human breast cancer development. The complementarities of these approaches have led to many examples of collaboration and cross-fertilization over the past decade that will continue in the proposed future funding period. In spite of extensive research over the past three decades, we still possess, at best, only a fragmentary understanding of how the different types of human breast cancers begin. The mechanisms that lead to the formation of these tumors must be elucidated at the level of molecules, cells, and ultimately tissues. The proposed research is focused on understanding the molecular and cellular mechanisms leading to breast cancer development, because it is clear that novel, truly effective prognostic tools and therapies can only be developed in the future if these disease-causing mechanisms are uncovered. Accordingly, a number of the research directions described herein have the potential, if successful, to suggest approaches for developing novel, improved diagnostic arid therapeutic strategies that can be used in the breast cancer clinic of the future.